On November 7, 2018 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, reported updated clinical results for the CYAD-01 program in solid tumors as well as translational research data presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 33rd Annual Meeting (Press release, Celyad, NOV 9, 2018, View Source [SID1234531096]).

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THINK Phase 1 Trial Update

Results from the dose-escalation trial were reported at SITC (Free SITC Whitepaper) (abstract P255). Overall 14 patients with relapsed/refractory disease (11 mCRC, two ovarian and one pancreatic) were enrolled in the trial, evaluating CYAD-01 without preconditioning chemotherapy at three different dose levels (300 million, 1 billion and 3 billion cells per injection) of one cycle of three administrations with two-week intervals. Patients treated at the highest dose level presenting signs of clinical activity (stable disease or greater) were eligible to receive a second cycle of treatment.
Overall four patients experienced confirmed disease stabilization (three mCRC patients and one patient with ovarian cancer) according to RECIST 1.1 criteria.
As a monotherapy treatment, CYAD-01 was well tolerated. Nine grade 3/4 treatment-related adverse events (AEs) were reported in five different patients including a grade 4 cytokine release syndrome (CRS) in dose level 3 considered as a dose-limiting toxicity (DLT). Five additional patients recruited at the same dose showed no further evidence of severe toxicity.
The peak level of peripheral CYAD-01 cells detected seem to correlate with the dose level and clinical response.
SHRINK Phase 1 Trial Update

The open-label, dose-escalation Phase 1 trial is assessing the safety and activity of CYAD-01 administered concurrently with FOLFOX chemotherapy in patients with liver metastases from colorectal cancer (CRC). Patients will receive six cycles of FOLFOX chemotherapy every two weeks and three administrations of CYAD-01 every two weeks 48 hours after the end of chemotherapy at cycles two, three and four. Based upon initial assessment of clinical activity, patients could be eligible to receive three additional administrations of CYAD-01 at the same dose level.
To date, enrollment of dose level one (100 million cells per injection) has been completed with three metastatic treatment-naïve patients. All patients have undergone resection without delays in surgery.
Initial activity results assessed by pathological response criteria showed all three patients achieved an objective clinical response, including one patient with a pCR and two patients with pPR.
Concurrent treatment of CYAD-01 with FOLFOX chemotherapy appears to be well tolerated, with no occurrence of serious AEs (SAEs) nor increase of treatment-related AEs rate.
In addition, the expansion of peripheral CYAD-01 cells with a concurrent administration of FOLFOX chemotherapy is similar to the one observed with the standalone CYAD-01.
Full data from the SHRINK Phase 1 trial are expected in mid-2019.
THINK CyFlu Phase 1 Cohort Update

In February 2018, the THINK trial was amended to include a cohort known as THINK CyFlu (previously referred to as DEPLETHINK-CRC). The cohort evaluates a single injection of CYAD-01 following treatment with the standard preconditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), or CyFlu. CyFlu is administered daily at days -5, -4 and -3 prior to treatment with CYAD-01.
To date, two patients have been enrolled into the cohort and completed the treatment schedule at the dose of 300 million cells per injection. Treatment with CYAD-01 following the standard preconditioning regimen of CyFlu was well tolerated with no occurrence of SAEs nor an increase of treatment-related AEs rate. As of November 9, the two enrolled patients were not yet evaluable for clinical response.
Preliminary translational data suggest an improvement in the cell expansion of CYAD-01 induced by the CyFlu preconditioning.
Full data from the THINK CyFlu Phase 1 cohort are expected in mid-2019.

Dr. Frédéric Lehmann, VP of Clinical Development & Medical Affairs at Celyad, commented, "Solid tumors remain the greatest current challenge for any T cell therapy. One of the major hurdles is the lack of suitable targets, and in our perspective, NKG2D ligands that are targeted by CYAD-01 represent an attractive family of targets on solid tumors that may be exploited by our clinical candidates. I am encouraged that to date CYAD-01 is well tolerated as a monotherapy for the treatment of mCRC, while preliminary observations of clinical activity in the form of disease stabilization imply that there is potential for the approach. Furthermore, the initial findings of clinical activity reported from the initial dose level of CYAD-01 when administered concurrently with standard-of-care chemotherapy in the SHRINK trial are encouraging and provide support for this view."

Celyad also highlighted several updates to the broader solid tumor development program and non-gene edited, allogeneic platforms.

LINK Phase 1 Trial Update

Following a strategic review of the CYAD-01 program in CRC, the Company has decided to stop enrollment of the LINK trial. The dose-escalation study had planned to assess the safety and clinical activity of multiple hepatic transarterial administrations of CYAD-01 in patients with unresectable liver metastases from CRC. To date, one patient in dose level one has been enrolled in the study.
alloSHRINK Phase 1 Trial Update

In July 2018, the U.S. Food and Drug Administration (FDA) permitted the Investigational New Drug (IND) application for CYAD-101, the world’s first non-gene edited, allogeneic CAR-T clinical candidate, to go into effect. As previously announced, CYAD-101 will initially be evaluated in the alloSHRINK trial.
alloSHRINK is an open-label, dose-escalation trial that will assess the safety and clinical activity of CYAD-101 administered concurrently with FOLFOX chemotherapy in patients with unresectable mCRC. Similar to the SHRINK trial for CYAD-01, patients will receive six cycles of FOLFOX chemotherapy every two weeks and three administrations of CYAD-01 every two weeks 48 hours after the initiation of chemotherapy cycles one, two and three.
Enrollment in the trial is expected to begin by year-end 2018 with topline data anticipated during the second half of 2019.
Next-Generation, Allogeneic shRNA Platform

In October 2018, Celyad announced it had entered into an exclusive agreement with Horizon Discovery Group for the use of its shRNA technology to generate a novel, next-generation, non-gene-edited allogeneic platform. Initial results from preclinical studies demonstrating the versatility of the shRNA technology in the allogeneic setting will also be presented at SITC (Free SITC Whitepaper) (abstract P220). Follow up data for the platform are expected in the first quarter of 2019.
"We are excited about the progress we have made thus far with our solid tumor program for lead candidate CYAD-01," said David Gilham, Ph.D., VP of Research and Development at Celyad. "We continue to investigate complementary regimens for CYAD-01 for the treatment of metastatic colorectal cancer that we believe may help to drive additional clinical activity in this devastating disease where a true unmet medical need exists. Additionally, CYAD-101 offers a first-in-class investigational allogeneic CAR-T for the treatment of mCRC and leverages our overall clinical experience within the indication while strategically positioning the Company to be a leading player in both the autologous and allogeneic CAR-T cell therapy space."

SITC Analyst/Investor Event

Celyad will host an Analyst/Investor event on Saturday, November 10, 2018, beginning at 12:30 p.m. ET to review data presented at SITC (Free SITC Whitepaper). The company presentation for the event will be available under Events & Webcasts in the Investors section of the Company’s website.

Background on CYAD-01 and CYAD-101

CYAD-01 is an investigational, autologous CAR-T therapy in which a patient’s T cells are engineered to express the chimeric antigen receptor NKG2D, a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands expressed on tumor cells. CYAD-101 is an investigational, non-gene edited, allogeneic (donor derived) CAR-T therapy that co-expresses the company’s CYAD-01 CAR-T construct and the novel inhibitory peptide TIM (T cell receptor [TCR] Inhibiting Molecule). TCR signalling is responsible for Graft versus Host Disease (GvHD). The expression of TIM reduces signalling of the TCR complex and could therefore reduce or eliminate GvHD in patients treated with CYAD-101

On November 9, 2018 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported data from the ongoing Phase 2 clinical trial of mocetinostat in combination with durvalumab (IMFINZI) in non-small cell lung cancer (NSCLC) patients at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 33rd Annual Meeting in Washington, D.C (Press release, Mirati, NOV 9, 2018, View Source [SID1234531095]). The data will be presented today in a poster and also in an oral presentation on Sunday, November 11th.

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Highlights from the Oral Presentation

The clinical trial is a Phase 2 study evaluating the efficacy and safety of mocetinostat in combination with durvalumab, an anti-PD-L1 immune checkpoint inhibitor, in patients with NSCLC who have experienced documented disease progression following prior treatment with an immune checkpoint inhibitor. As of the data cut-off date of October 2, 2018:

29 patients were evaluable for response with at least one radiographic scan. Patients had a median of two lines of previous therapy.
12/29 evaluable patients demonstrated tumor reductions.
6/29 evaluable patients demonstrated tumor reductions of greater than 30%.
5/29 evaluable patients achieved a confirmed Partial Response (PR).
4/29 evaluable patients, including 2 responding patients, remained on treatment at the time of data cut-off.
A preliminary Kaplan-Meier estimate of median duration of response was greater than 5 months.
The combination has been well-tolerated and most adverse events (AEs) were grade 1 or 2.
"The combination of mocetinostat with durvalumab demonstrated clinical benefit in this difficult to treat population of checkpoint inhibitor refractory NSCLC patients," said Charles Baum, M.D., Ph.D., President and Chief Executive Officer at Mirati Therapeutics. "While these results are promising, we have made the strategic portfolio decision to prioritize sitravatinib for further development in the treatment of checkpoint inhibitor refractory patients and plan to explore collaborative opportunities to further develop mocetinostat."

The Company recently announced plans to initiate a Phase 3 clinical trial comparing sitravatinib in combination with checkpoint inhibitor therapy to docetaxel in second line checkpoint inhibitor refractory NSCLC patients in the first half of 2019. In addition, the Company also announced plans to initiate a Phase 1/2 clinical trial of MRTX849, an oral inhibitor of KRAS G12C, in patients with NSCLC, colorectal cancer, and other solid tumors that harbor the G12C mutation. Trial initiation is planned for early 2019 after the investigational new drug (IND) allowance letter is received from the U.S. Food and Drug Administration (FDA) for the application that was filed in October 2018.

About Mocetinostat

Mocetinostat is an oral, Class I and IV selective histone deacetylase (HDAC) inhibitor. Inhibition of histone acetylation is predicted to enhance the recognition of tumor cells by anti-tumor T cells and reverse immunosuppressive factors in the tumor microenvironment. Mocetinostat is being evaluated in a Phase 2 clinical trial in combination with durvalumab (IMFINZI) in non-small cell lung cancer (NSCLC) patients who have experienced disease progression following prior treatment with a checkpoint inhibitor.

About Sitravatinib

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being evaluated in combination with nivolumab (OPDIVO), an anti-PD-1 checkpoint inhibitor, in patients who have experienced documented disease progression following treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion clinical trial emphasizing enrollment of patients whose tumors harbor specific mutations in the CBL protein. When CBL is inactivated by mutation, multiple RTKs, including TAM, VEGFR2 and KIT, are dysregulated and may act as oncogenic tumor drivers in NSCLC and melanoma. Sitravatinib potently inhibits these RTKs and is being investigated as a treatment option for cancer patients with CBL mutations.

About MRTX849

MRTX849 is an orally-available small molecule that potently and selectively inhibits a form of KRAS which harbors a substitution mutation (G12C). KRAS G12C mutations are present in approximately 14% of NSCLC adenocarcinoma patients and 5% of colorectal cancer patients. Tumors characterized by KRAS G12C mutations are commonly associated with poor prognosis and resistance to therapy, and patients with these mutations have few treatment options. MTRX849 has demonstrated broad-spectrum tumor regression in a large cohort of KRAS G12C positive, pre-clinical in-vivo human tumor models. MRTX849 demonstrated complete regression of tumors in a subset of models at well-tolerated dose levels. Early proof-of-concept clinical data is anticipated in 2019.

On November 9, 2018 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported interim data Phase 1 dose-escalation study of CDX-1140, a fully human agonist anti-CD40 antibody (Press release, Celldex Therapeutics, NOV 9, 2018, View Source [SID1234531094]). CD40, expressed on dendritic cells and other antigen presenting cells, has long been an important target for immunotherapy, as it plays a critical role in the activation of innate and adaptive immune responses. The data were presented in a poster session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 33rd Annual Meeting.

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"CDX-1140 was specifically designed to balance systemic dosing and safety, which has proven elusive for CD40-targeted activating therapeutics," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "We have completed four of the potential eight monotherapy dose levels and, to date, CDX-1140 has been well tolerated. Importantly, we are observing dose-dependent biological effects consistent with CD40-mediated immune cell activity. Based on these positive findings, we have expanded development of the program and recently initiated a combination cohort with CDX-301, our dendritic cell growth factor, to increase the number of dendritic cells which are critical to initiating antitumor immunity and a key target for CDX-1140. We also expanded the study to include patients with non-Hodgkin’s lymphoma as our preclinical work has demonstrated that CDX-1140 has direct killing effect on CD40-expressing NHL cells. We look forward to continued data updates from this study in the first half of 2019."

Potent CD40 agonist antibodies have shown encouraging results in early clinical studies; however, systemic toxicity associated with broad CD40 activation has limited their dosing. CDX-1140 has unique properties relative to other CD40 agonist antibodies: potent agonist activity resulting in dendritic cell and B cell activation is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation; CD40 ligand (CD154) binding is not blocked, allowing potential synergistic, antigen-specific agonist activity; and the antibody promotes strong immune activation without significant adverse events in preclinical toxicology studies.

Study Highlights:
Seventeen patients with solid tumors were enrolled at the time of data analysis (n=13 monotherapy; n=4 combination). Four single-agent dosing cohorts have completed (0.01; 0.03, 0.09 and 0.18 mg/kg) and enrollment to the 0.36 mg/kg monotherapy cohort is ongoing. Enrollment to the first CDX-1140/CDX-301 combination cohort is ongoing (0.09 mg/kg and 75 ug/kg, respectively). Dose dependent biological effects consistent with CD40-mediated immune activation have been observed in the study and no maximum tolerated dose (MTD) has been identified to date. Continued enrollment is ongoing to define the MTD and select a dose for disease-specific expansion cohorts that will be monitored for clinical activity.

CDX-1140 has been well tolerated to date. One patient experienced a grade 3 dose-limiting toxicity (DLT) (pneumonitis and hypoxia) at the single-agent 0.18 mg/kg dose. Per protocol, three additional patients were enrolled in the cohort and no additional DLTs have been observed in this or subsequent cohorts.

There have been no significant drug-related changes observed to date in liver function tests or platelets, which have been observed with other CD40 agonists.

Transient dose-dependent pharmacodynamic effects have been observed including activation of immune cells and increases in pro-inflammatory cytokines and chemokines in the blood, which are consistent with CD40-mediated immune activation and the hypothesis that CDX-1140 may achieve dose levels optimal for systemic exposure.
A combination cohort with Celldex’s dendritic cell growth factor CDX-301 has been added to the CDX-1140 study. Dendritic cells, which express CD40, are rarely present or completely absent within the tumor microenvironment and are critical for initiating anti-tumor immunity. CDX-301 is being utilized to increase the number of dendritic cells in blood and tissue available for CDX-1140 activation. CDX-1140 should, in turn, activate the dendritic cells, an important step for enhancing anti-tumor immune responses. While this combination cohort just recently opened to enrollment, preliminary evidence of enhanced immune activation has been observed. Patients continue to be monitored for toxicity with no DLT observed to date.
The study has also been amended to allow for the inclusion of patients with CD40-expressing B cell lymphomas (subtypes of non-Hodgkin lymphoma or NHL) in up to two single-agent cohorts. Both immune activation and direct killing of CD40-expressing NHL cells by CDX-1140 have been shown to contribute to antitumor activity. Several B cell lymphomas, including diffuse large B-cell lymphoma and follicular lymphoma, also express both CD40 and CD27. Celldex’s varlilumab is a potent CD27 agonist and has been shown to synergize with CDX-1140 in NHL models and may be evaluated in combination with CDX-1140 in the future.
About CDX-1140
CDX-1140 is a fully human antibody targeted to CD40, a key activator of immune response that is found on dendritic cells, macrophages and B cells and is also expressed on many cancer cells. Potent CD40 agonist antibodies have shown encouraging results in early clinical studies; however, systemic toxicity associated with broad CD40 activation has limited their dosing. CDX-1140 has unique properties relative to other CD40 agonist antibodies: potent agonist activity resulting in dendritic cell and B cell activation is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation; CD40 ligand (CD154) binding is not blocked, allowing potential synergistic, antigen-specific agonist activity; and the antibody promotes strong immune activation without significant adverse events in preclinical toxicology studies. CDX-1140 has also shown direct antitumor activity in preclinical lymphoma models. Celldex believes that the potential for CDX-1140 will be best defined in combination studies with other immunotherapies, including CDX-301, Celldex’s dendritic cell growth factor, varlilumab, Celldex’s potent CD27 agonist, checkpoint blockade, radiation and other conventional cancer treatments.

On November 9, 2018 Immune Design (Nasdaq: IMDZ), an immunotherapy company focused on next-generation therapies in oncology, reported that Carlos Paya, M.D., Ph.D., President and Chief Executive Officer, will present at the Jefferies 2018 London Healthcare Conference on Wednesday, November 14, 2018 at 9:40 a.m. GMT / 4:40 a.m. ET (Press release, Immune Design, NOV 9, 2018, View Source [SID1234531093]).

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A live webcast of the presentation will be available online from the investor relations page of the company’s corporate website at View Source After the live webcast, an archive of the presentation will be available on the company website for 30 days.

On November 9, 2018 Aurinia Pharmaceuticals Inc., (NASDAQ:AUPH)(TSX:AUP) reported its Chairman and CEO, Richard Glickman, will participate in two upcoming investor conferences (Press release, Aurinia Pharmaceuticals, NOV 9, 2018, View Source [SID1234531092]).

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Wednesday, November 14, 2018, Aurinia will present a company overview at the Jefferies 2018 London Healthcare Conference in London, UK at 10:00am GMT. The presentation will be webcast live and can be accessed via the investor section of the Aurinia website, www.auriniapharma.com. A replay of will also be archived on the site following the event.

Tuesday, November 27, 2018, Aurinia will participate in One-on-One Meetings at the Evercore ISI HealthCONx Conference in Boston, MA.